Interleukin-16 (IL-16), previously named lymphocyte chemoattractant factor (or LCF), is a pro-inflammatory lymphokine with chemoattractant activity for resting CD4+ T lymphocytes. Subsequent studies indicate that IL-16 activates signal transduction in CD4+ target cells including monocytes, eosinophils and pro-B cells, and stimulates a variety of biological activities in addition to chemotaxis. Among these activities are inhibition of retroviral replication (Maciaszek, et al., J. Immunol. 158:5, 1997; Zhou, et al., Nature Medicine 3:659, 1997 and Baier, et al., Nature 378:563, 1995), upregulation of IL-2R and synergy with IL-2 for CD4+ T cell proliferation (Parada, et al., J. Immunol. 160:2115, 1998), induction of RAG-1 and RAG-2 expression in CD4+ pro-B cells (Szabo, et al., J. Immunol., 161:2248, 1998), and transient inhibition of Mixed Lymphocyte Reaction (MLR)(Theodore, et al., J. Immunol. 157:1958, 1996). Investigation of certain human diseases and experimental murine models indicates that IL-16 participates in inflammatory conditions characterized by tissue recruitment of CD4+ T lymphocytes and other CD4+ cell types. Conditions where IL-16 has been identified by ELISA and/or bioassay of body fluids, or by immunohistochemical and in situ hybridization techniques, include bronchial asthma (Laherge et al., Am. J. Respir. Cell. Mol. Biol. 17: 193, 1997), inflammatory bowel disease (Keates et al., Gastroenterology 112, A110, 1997), Graves' disease (Cruikshank et al., J. Allergy Clin. Immunol. 99: 554, 1997), multiple sclerosis (Biddison et al., J. Immunol. 158: 3046, 1997) and bullous pemphigoid (Center et al., J. Invest. Dermatol. 81: 204, 1983). IL-16 is also implicated in the pathogenesis of rheumatoid arthritis (Klimiuk et al., J. Immunol. 162: 4293-4299, 1999) and lupus (Lee et al., British J. Rheumatology 37: 1334-1337, 1998). Thus, it would be desirable to identify and/or generate reagents capable of interfering with the IL-16 activity for the purpose of treating inflammatory diseases.
The predicted amino acid sequence of IL-16 contains a central PDZ module, and structural studies confirm that IL-16 assumes a core PDZ-like conformation with flexible N-terminal and C-terminal tails of 17 and 14 residues, respectively (Muhlhahn et al., Nature Structural Biology 5:682, 1998)). A synthetic oligopeptide corresponding to the 16 C-terminal amino acids of human IL-16 (Arg106 to Ser121) has been reported to inhibit the chemoattractant activity of natural and recombinant human or murine IL-16 (Keane et al., J. Immunol. 160:5945, 1998).
The present invention demonstrates that a series of peptides corresponding to native or substituted sequences of the C-terminus of IL-16 can inhibit IL-16 activity. Compositions and methods useful for treating IL-16 mediated disorders are exploited using these peptides.